Imaging of vesicular monoamine transporter 2 (VMAT2) sites in the brain by [C-11]DTBZ (dihydrotetrabenazine) in conjunction with PET (positron emission tomography) is useful in the diagnosis and monitoring of neurodegenerative diseases such as Parkinson's and Huntington's diseases. In addition, PET imaging of VMAT2 binding sites is also important for understanding the mechanisms of regulation of monoamines in the brain and its relationship with drug abuse and psychiatric disorders. Since C-11 is a short lived isotope with a half-life of 20 minutes the usefulness of this tracer is limited by a requirement for an onsite cyclotron and a team of skilled researchers. To overcome the technical barrier of using this otherwise very useful tracer and to provide ready access for PET clinics to perform this type of study, F-18 DTBZ analogs with a half-life of 110 min are proposed. The new VMAT2 imaging agents could be manufactured by radiopharmacies and distributed widely on a routine basis. Synthesis, radiolabeling and resolution of diastereomers and enantiomers of novel F-18 labeled DTBZ derivatives are proposed. They will be selected and optimized by comparing binding affinity using in vitro binding assay. In vivo biodistribution study in the brain of normal and lesioned rats after iv injection of the tracers will be determined. In vivo PET imaging study and kinetic modeling of VMAT2 in the brain of non-human primates will be evaluated for selected candidates. Ultimately, it is expected that a VMAT2/PET imaging agent will be developed for phase I clinical trial by the end of the third year of this project. The objective of this project is to solve a problem in supplying an effective PET tracer for routine clinical use. If successfully developed, the proposed novel tracers may have a high impact on the diagnosis of various abnormalities of brain function and diseases related to changes of the storage of monoamine neurotransmitters. This is a collaborative project between the research groups of the PI in University of Pennsylvania and Dr. Michael Kilbourn, University of Michigan. Combining the strength of two laboratories will greatly enhance the chance of reaching the goals proposed in this project.